Advertisement

Clinical Pharmacokinetics

, Volume 43, Issue 12, pp 823–832 | Cite as

Effect of Mycophenolate Mofetil on the Pharmacokinetics of Antiretroviral Drugs and on Intracellular Nucleoside Triphosphate Pools

  • Sanjay U. C. Sankatsing
  • Patrick G. Hoggard
  • Alwin D. R. Huitema
  • Rolf W. Sparidans
  • Stephen Kewn
  • Kristel M. L. Crommentuyn
  • Joep M. A. Lange
  • Jos H. Beijnen
  • David J. Back
  • Jan M. Prins
Original Research Article

Abstract

Objective

To study the effect of mycophenolate mofetil therapy on the pharmacokinetic parameters of a number of antiretroviral drugs, on intracellular pools of deoxycytidine triphosphate (dCTP) and deoxyguanosine triphosphate (dGTP), and on intracellular concentrations of the triphosphate of lamivudine (3TCTP).

Design

Randomised pharmacokinetic study.

Participants

Nineteen HIV-1-infected patients.

Methods

Antiretroviral-naive men starting treatment with didanosine 400mg once daily, lamivudine 150mg twice daily, abacavir 300mg twice daily, indinavir 800mg twice daily, ritonavir 100mg twice daily and nevirapine 200mg twice daily were randomised to a group with or without mycophenolate mofetil 500mg twice daily. After 8 weeks of therapy, the plasma pharmacokinetic profiles of mycophenolic acid (the active metabolite of mycophenolate mofetil), abacavir, indinavir and nevirapine, and triphosphate concentrations (dCTP, dGTP and 3TCTP) in peripheral blood mononuclear cells, were determined.

Results

Nine of the 19 patients received mycophenolate mofetil. There was no difference in plasma clearance of indinavir or abacavir between the two groups. The clearance of nevirapine was higher in patients using mycophenolate mofetil (p = 0.04). In 12 patients, of whom five also received mycophenolate mofetil, intracellular triphosphates were measured. There was no significant difference in intracellular dCTP, dGTP or 3TCTP concentrations between the two groups. Conclusion: In this small cohort of patients, mycophenolate mofetil therapy reduced the plasma concentration of nevirapine but had no effect on plasma concentrations of indinavir and abacavir. There were no consistent effects of mycophenolic acid on the intracellular concentrations of dCTP, dGTP or 3TCTP.

Keywords

Nevirapine Mycophenolate Mofetil Indinavir Abacavir Mycophenolic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank Marijke Roos, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands, for measuring lymphocyte proliferation. This study was financially supported by a private foundation that wishes not to be named.

Part of this study was presented at the 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA in February 2003.

The authors have no conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    van Praag RM, Wit FW, Jurriaans S, et al. Improved long-term suppression of HIV-1 replication with a triple-class multidrug regimen compared with standard of care antiretroviral therapy. AIDS 2002; 16(5): 719–25PubMedCrossRefGoogle Scholar
  2. 2.
    Weverling GJ, Lange JM, Jurriaans S, et al. Alternative multidrug regimen provides improved suppression of HIV-1 replication over triple therapy. AIDS 1998; 12(11): F117–22PubMedCrossRefGoogle Scholar
  3. 3.
    Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med 1999; 340(21): 1605–13PubMedCrossRefGoogle Scholar
  4. 4.
    Zack JA, Arrigo SJ, Weitsman SR, et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 1990; 61(2): 213–22PubMedCrossRefGoogle Scholar
  5. 5.
    De Boer RJ, Boucher CA, Perelson AS. Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine. AIDS 1998; 12(13): 1567–70PubMedCrossRefGoogle Scholar
  6. 6.
    Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science 1994; 266(5186): 801–5PubMedCrossRefGoogle Scholar
  7. 7.
    Havlir DV, Gilbert PB, Bennett K, et al. Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression. AIDS 2001; 15(11): 1379–88PubMedCrossRefGoogle Scholar
  8. 8.
    Margolis D, Heredia A, Gaywee J, et al. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. J Acquir Immune Defic Syndr 1999; 21(5): 362–70PubMedGoogle Scholar
  9. 9.
    Chapuis AG, Paolo RG, D’Agostino C, et al. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med 2000; 6(7): 762–8PubMedCrossRefGoogle Scholar
  10. 10.
    Becker BN. Mycophenolate mofetil. Transplant Proc 1999; 31(7): 2777–8PubMedCrossRefGoogle Scholar
  11. 11.
    Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000; 47(2–3): 85–118PubMedCrossRefGoogle Scholar
  12. 12.
    Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993; 136: 5–28PubMedCrossRefGoogle Scholar
  13. 13.
    Faletto MB, Miller WH, Garvey EP, et al. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother 1997; 41(5): 1099–107PubMedGoogle Scholar
  14. 14.
    Stein DS, Moore KH. Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians. Pharmacotherapy 2001; 21(1): 11–34PubMedCrossRefGoogle Scholar
  15. 15.
    Hossain MM, Coull JJ, Drusano GL, et al. Dose proportional inhibition of HIV-1 replication by mycophenolic acid and synergistic inhibition in combination with abacavir, didanosine, and tenofovir. Antiviral Res 2002; 55(1): 41–52PubMedCrossRefGoogle Scholar
  16. 16.
    Halpern SD, Ubel PA, Caplan AL. Solid-organ transplantation in HIV-infected patients. N Engl J Med 2002; 347(4): 284–7PubMedCrossRefGoogle Scholar
  17. 17.
    Gummert JF, Barten MJ, Sherwood SW, et al. Pharmacodynamics of immunosuppression by mycophenolic acid: inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics. J Pharmacol Exp Ther 1999; 291(3): 1100–12PubMedGoogle Scholar
  18. 18.
    Roos MT, Prins M, Koot M, et al. Low T-cell responses to CD3 plus CD28 monoclonal antibodies are predictive of development of AIDS. AIDS 1998; 12(14): 1745–51PubMedCrossRefGoogle Scholar
  19. 19.
    Sparidans RW, Hoetelmans RM, Beijnen JH. Liquid Chromatographic assay for simultaneous determination of abacavir and mycophenolic acid in human plasma using dual spectrophotometric detection. J Chromatogr B Biomed Sci Appl 2001; 750(1): 155–61PubMedCrossRefGoogle Scholar
  20. 20.
    Crommentuyn KM, Rosing H, Nan-Offeringa LG, et al. Rapid quantification of HIV protease inhibitors in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. J Mass Spectrom 2003; 38(2): 157–66PubMedCrossRefGoogle Scholar
  21. 21.
    van Heeswijk RP, Hoetelmans RM, Meenhorst PL, et al. Rapid determination of nevirapine in human plasma by ion-pair reversed-phase high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Sci Appl 1998; 713(2): 395–9PubMedCrossRefGoogle Scholar
  22. 22.
    Kewn S, Hoggard PG, Sales SD, et al. Development of enzymatic assays for quantification of intracellular lamivudine and carbovir triphosphate levels in peripheral blood mononu-clear cells from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2002; 46(1): 135–43PubMedCrossRefGoogle Scholar
  23. 23.
    Sankatsing SUC, Jurriaans S, van Swieten P, et al. Highly active antiretroviral therapy with or without mycophenolate mofetil in treatment-naive HIV-1 patients. AIDS. In pressGoogle Scholar
  24. 24.
    Sankatsing SU, Prins JM. Agranulocytosis and fever seven weeks after starting abacavir. AIDS 2001; 15(18): 2464–5PubMedCrossRefGoogle Scholar
  25. 25.
    Brunet M, Martorell J, Oppenheimer F, et al. Pharmacokinetics and pharmacodynamics of mycophenolic acid in stable renal transplant recipients treated with low doses of mycophenolate mofetil. Transpl Int 2000; 13 Suppl. 1: S301–5PubMedCrossRefGoogle Scholar
  26. 26.
    Boehringer Ingelheim Pharmaceuticals. Viramune® (nevirapine): product information. Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals, 1999Google Scholar
  27. 27.
    Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34(6): 429–55PubMedCrossRefGoogle Scholar
  28. 28.
    Cheeseman SH, Hattox SE, McLaughlin MM, et al. Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob Agents Chemother 1993; 37(2): 178–82PubMedCrossRefGoogle Scholar
  29. 29.
    van Gelder T, Klupp J, Barten MJ, et al. Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid. Ther Drug Monit 2001; 23(2): 119–28PubMedCrossRefGoogle Scholar
  30. 30.
    Daluge SM, Good SS, Faletto MB, et al. 1592U89, a novel carbocyclic nucleoside analog with potent, selective antihuman immunodeficiency virus activity. Antimicrob Agents Chemother 1997; 41(5): 1082–93PubMedGoogle Scholar
  31. 31.
    Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2002; 31(1): 45–9PubMedCrossRefGoogle Scholar
  32. 32.
    Gao WY, Johns DG, Chokekuchai S, et al. Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2′,3′-dideoxynucleoside activities against replication of human immunodeficiency virus. Proc Natl Acad Sci U S A 1995; 92(18): 8333–7PubMedCrossRefGoogle Scholar
  33. 33.
    Hoggard PG, Kewn S, Maherbe A, et al. Time-dependent changes in HIV nucleoside analogue phosphorylation and the effect of hydroxyurea. AIDS 2002; 16(18): 2439–46PubMedCrossRefGoogle Scholar
  34. 34.
    Miller WH, Daluge SM, Garvey EP, et al. Phosphorylation of carbovir enantiomers by cellular enzymes determines the stereoselectivity of antiviral activity. J Biol Chem 1992; 267(29): 21220–4PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Sanjay U. C. Sankatsing
    • 1
    • 2
  • Patrick G. Hoggard
    • 3
  • Alwin D. R. Huitema
    • 4
  • Rolf W. Sparidans
    • 5
  • Stephen Kewn
    • 3
  • Kristel M. L. Crommentuyn
    • 4
  • Joep M. A. Lange
    • 1
    • 2
  • Jos H. Beijnen
    • 4
    • 5
  • David J. Back
    • 3
  • Jan M. Prins
    • 2
  1. 1.International Antiviral Therapy Evaluation CenterAmsterdamThe Netherlands
  2. 2.Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of Pharmacology and TherapeuticsUniversity of LiverpoolLiverpoolUK
  4. 4.Department of Pharmacy and PharmacologySlotervaart HospitalAmsterdamThe Netherlands
  5. 5.Department of Drug ToxicologyUtrecht UniversityUtrechtThe Netherlands

Personalised recommendations